A jigsaw with unknown pieces

Depression is a common illness all over the world. According to the statistics, one in four women and one in seven men are affected at some point in their lives. The World Health Organisation (WHO) classes depression as the third most important cause of ill health in the world and it is estimated that around 350 million people are suffering from the illness.

DEPRESSION CAN AFFECT people of all ages, even children and adolescents, but the risk increases with advancing age. The consequences are enormous in terms of reduced quality of life, both for patients themselves and their relatives, and the increased risk of suicide. On the whole, it is actually rather uncommon for depressed people to take their own lives, but the overwhelming majority of those who commit suicide are suffering from depression. According to some experts, it is probably also very uncommon for someone to take their own life without having first been affected by a depressive illness.

In the West, depression is also a very costly illness. In Sweden, it has been calculated that the illness costs a total of SEK 35 billion per year, with 88 per cent of this taking the form of indirect costs, primarily those caused by long periods of sick leave.

WHO's forecasts indicate that depression will have advanced to take first place on the list of global causes of ill health by 2030. But luckily, this is not because of any global depression pandemic that is taking place.

“Instead, it is because other causes of ill health are on their way down. Progress is being made in terms of cardiovascular care and in terms of the care of newborns in developing countries which is reducing mortality rates. But the equivalent progress is not being made in the field of depression,” says Johan Lundberg, docent at the Department of Clinical Neuroscience, Karolinska Institutet and consultant physician and head of the Section for Affective Disorders at Northern Stockholm Psychiatry.

AND SO IT IS. Since the monoamine hypothesis was formulated in the 1960s, which states that depression is due to a deficiency of monoamine signalling substances such as serotonin, noradrenalin and dopamine in the brain, no major breakthroughs have been made. The hypothesis concerning the central role of the monoamines in depression has actually resulted in a large number of new medications for depression such as Prozac, Cipramil and Zoloft. The problem is that it takes at least two weeks before they have any effect and, even worse, it is far from the case that everyone is helped by them. In reality, only about one third become free of depression, one third gain some relief from their symptoms, while the final third do not improve at all.

“There are two problems here. The first is that when we meet a patient, we do not know which treatment will help. We treat on the basis of what is available and what people want to have and test our way forward,” says Johan Lundberg.

When it takes at least two weeks before any effect can be seen, this means of course that it can take quite a long time to find the correct treatment.

“The second problem is that even after having tried all the available treatments, up to one third of patients are not helped at all,” he says.

And it is these problems that current research is primarily focused on.

“We have both a need to know which treatments help each individual patient and a need to develop new treatments that help those who are not helped by those we already have. For both of these reasons, we need to understand more about the mechanisms behind depression,” says Johan Lundberg.

ONE FURTHER complicating factor is that what is diagnosed as depression probably actually has several different causes.

“The diagnosis depression is a syndrome that is defined in a consensus decision by experts in the field. Of course, the most important symptom is that the patient is suffering from a depressed mood for a long time. But a depressed mood is one of nine symptoms, five of which are required in order to fulfil the diagnostic criteria for depression. The others include an increased or decreased need for sleep, a reduced or increased appetite; both changes are accepted symptoms of depression. Accordingly, it is possible to understand what a mixed group patients with depression are and how difficult it is to find common denominators in the illness mechanisms,” says Johan Lundberg.

He argues that the imprecise diagnosis slows the pace of research as it makes it more difficult to interpret research findings, at the same time as this may be an explanation for why the same treatment does not help all patients. But the question is how does it actually hang together and how can patients be defined more specifically?

Everyone now agrees that the monoamine hypothesis does not paint the whole picture. It is thus highly unlikely that a serotonin deficiency in the synapses causes depression. The big question for researchers is therefore: What is it instead? But there is still a distinct lack of knowledge about this.

“It is like we have small individual pieces from a 100,000-piece jigsaw puzzle,” says Johan Lundberg.

But perhaps the few pieces that the researchers do have can show where they should look further. The medications most commonly used today to combat depression, known as selective serotonin reuptake inhibitors (SSRIs), act by inhibiting the uptake of serotonin in the synaptic cleft, increasing the quantity of serotonin there; completely in accordance with the monoamine hypothesis. But there is another antidepressant, tianeptine (Coaxil), developed in France more than 25 years ago and approved in some EU countries, but not Sweden, which is about as effective as the SSRIs, but which has the opposite effect. Tianeptine is a serotonin reuptake enhancer; it thus reduces the amount of serotonin in the synaptic cleft and yet has an equivalent antidepressant effect. A fact that really challenges the monoamine hypothesis.

“The effect of serotonin in the synaptic cleft is presumably not as important to the antidepressant effect of serotonin,” says Per Svenningsson, professor at the Department of Clinical Neuroscience, Karolinska Institutet.

He has studied tianeptine's mechanism of action in detail and in 2010 published evidence that the substance also has, aside from its effects on the serotonin system, an effect on what is known as the glutamate system.

“Among the findings from my lab is that tianeptine also stimulates AMPA glutamate receptors and that this is important for the antidepressant effect,” he says.

The glutamate system is another signalling system in the brain that has now moved into the position of prime suspect in the hunt for the key mechanism of depression. This has happened because of progress such as the American psychiatrist Robert Berman being able to demonstrate, in a small study of seven depressed patients in 2000, that an injection of the drug ketamine (Ketalar) had an antidepressant effect within two hours that lasted for two weeks. This was something completely different from the SSRI preparations, which take at least two weeks to have an effect, if there even is one.

BUT UNFORTUNATELY ketamine is not a solution to the problem. IT is an old substance from the 1960s that has been used for purposes such as putting patients to sleep prior to surgery and reducing chronic, hard-to-treat pain. The substance must be injected by healthcare personnel and the exhaustive list of side effects indicate that it is not uncommon for the drug to cause confusion, hallucinations and even induced psychosis among patients, as well as increasing blood pressure and causing muscle cramps. Ketamine also has the potential to be misused as a hallucinogen and many overdoses, drownings, road traffic accidents and suicides are ascribed to its misuse. Hardly a dream medication to hand out widely to the large number of people with depression, not even the one third of them who are not helped by current drugs. But it is still the case that ketamine is used, under expert supervision, to treat patients in Sweden.

The important aspect of the ketamine finding is not the treatment potential, but the rapid effect it has on depression. Ketamine is what is known as a NMDA receptor antagonist, a substance that inhibits the receptor NMDA, which has a central role in the glutamate system. The glutamate system thus appears to be a mechanism that is more central to depression than the serotonin system, even though there is also evidence that they are linked.

“It is believed that serotonin changes the synapses. We know that it takes several weeks before there is an effect so serotonin probably acts as a trigger that stimulates other signalling systems. There is data that indicate the glutamate system may be involved here as well,” says Per Svenningsson.

He has himself discovered a protein that is called p11, which could be an intermediary in this interaction. He found that the p11 protein is important in the process of placing certain serotonin receptors in the cell surface, among them a receptor called 5-HT1B. He has also demonstrated that p11 levels are much lower in depressed patients and in animal models.

“All antidepressants I have tested increase the quantity of p11, which in turn increases the number of receptors, reinforcing the serotonergic signal,” says Per Svenningsson.

RECENTLY, IT HAS ALSO BEEN discovered that p11 reinforces the signal in the glutamate system. One hypothesis is therefore that antidepressant drugs upregulate p11, which reinforces the signal in both the serotonin system and the glutamate system and that this is part of the antidepressant effect. In addition, p11 has further properties that may be significant.

“The protein plays an important role in epigenetic mechanisms that control gene regulation,” says Per Svenningsson.

This means that p11 is an important factor in the process of turning on or off one or more genes, something that researchers have realised is entirely possible in recent times. Very simply, epigenetics can be described as there being a type of switch sitting in front of genes that determines whether or not they will be read. Under certain conditions, the body turns on the switch so that the gene in question starts being read. The information in the gene is instructions for manufacturing a protein that has various effects inside the cell. If a certain gene is turned on, a certain protein is manufactured that has certain effects in the body.

“We do not know which genes they are, but this could partly explain why it takes such a long time for the antidepressant effect of an SSRI to kick in. A new gene programme must be activated,” says Per Svenningsson.

One of the functions of p11 was to upregulate the serotonin receptor 5-HT1B. It is now known that 5-HT1B receptors are also found on nerve cells in the glutamate system and that some of the effect of ketamine appears to occur via these specific receptors.

In addition, Johan Lundberg's group have been able to show specifically that patients with depression appear to have a smaller number of 5-HT1B receptors in several different parts of the brain that are already known to be affected in cases of depression.

“We have therefore applied for further grants in order to study the 5-HT1B receptor's role in mice and in humans. This could result in a treatment for depressed people using a drug that has the positive effects of ketamine, but without many of the side effects and dependence problems,” he says.

BUT DRUGS ARE NOT the only means by which to help people with depression. The very best of the current treatments, according to researchers and the science, is electroconvulsive therapy (ECT). This involves short pulses of current being passed through the brain with the help of electrodes attached to the head. The treatment induces a controlled convulsion that lasts for between 15 and 60 seconds. A course of treatment for depression often involves between six and eight treatments.

ECT is a little bit special because it works best on the most severely ill patients, those who should normally be hardest to treat.

It is a completely remarkable experience to see the effect on a really ill patient who almost doesn't respond when addressed. The patient gets well in a few days.

“It is a completely remarkable experience to see the effect on a really ill patient who almost doesn't respond when addressed. The patient gets well in a few days,” says Mikael Landén, professor of general psychiatry at the Department for Medical Epidemiology and Biostatistics, Karolinska Institutet.

He conducts research into ECT, its mechanism and which patients are best suited to the treatment. As is the case for drug treatment, ECT is better at helping some patients than others. The basic rule today is that the deeper the depression and the more clearly delimited the episode is, in other words that the patient was healthy and then suddenly descended into a deep depression, the better the effect. ECT also has a number of troublesome side effects such as memory disturbances, but this only affects a small proportion of patients. Consequently, Mikael Landén takes blood samples before and after ECT in order to try and find something that can indicate who is at risk of side effects.

“Our dream scenario is to find a marker that shows which patients are extra sensitive to memory side effects and then perhaps we can think again before giving them ECT,” he says.

No one knows exactly how ECT works.

“There are effects on the old common monoamine system, but there are also other effects in the glutamate system, opioid system and so forth. What we cannot say exactly is what the active ingredients are, but it is perhaps not one individual factor, instead what is needed is the total combination of factors.”

Mikael Landén argues that the major challenge to getting somewhere with the treatment of depression, regardless of whether this is drugs, therapy or ECT, is to gain clarity about what depression actually is.

“All those working on depression have a sense that it is not one thing but many. You could say that we are sort of at the level of fever within psychiatry. If you have 100 patients with fever, you give them antibiotics and one third of them will get well as they have a bacterial infection. But then you have those who are suffering from a viral infection and they don't get well at all, and then those that have a fever caused by rheumatism or something similar and they don't get well either,” he says.

There is a great deal that points to there being several different mechanisms behind the depressive symptoms. Aside from faulty regulation in the glutamate system, depression can also have inflammatory causes. Researchers have found elevated levels of inflammatory molecules in the brains of depressed people. Mikael Landén's research is also following a path in this area.

“We have looked at the cerebrospinal fluid of people with depression or bipolar disorder and found elevated levels of inflammatory substances. But these are nothing like the levels seen in patients with MS or similar diseases,” he says.

IT IS THUS NOT a question of a regular inflammation in the brain, rather it means that the inflammatory molecules also have other tasks, he explains. We know that the young brain has a large surplus of synapses that are then cleared away by the immune system, improving the brain's function. One hypothesis is that the system has ended up a little out of whack and clears away a little bit too much, for a little too long. There are a large number of animal experiments that support this hypothesis, as well as clinical evidence, explains Per Svenningsson.

“Attempts have been made to treat patients with depression using an anti-inflammatory drug, and this worked for those patients who had measurable signs of mild inflammation.”

Another somewhat notable point is that depression is about twice as common among women as it is among men. No one knows why this is. Nor does it appear to have any significance to treatment, with both sexes responding equally well, or equally poorly. However, if you take one step back, a pattern emerges.

“The overall risk for anxiety, depression and dependence is about the same for men and women, but men are much more likely to suffer from dependence, while women are much more likely to suffer from depression and anxiety,” says Johan Lundberg.

One further alternative to drug treatment for patients with depression is cognitive behavioural therapy (CBT). However, there has long been a conflict between pharmacologists and psychologists about which treatment is actually the best. The conflict originates in the fact that the effects of drugs and therapy are investigated in different ways. Drugs must always be tested against a placebo, whereas the same requirement is not in place for therapy, which can be tested against nothing, which means that the measured effects appear much greater and the comparison is erroneous. At the root of this are question of which treatment actually helps the patients best and how resources are to be allocated between the different treatments.

BUT IT NOW APPEARS that some kind of thaw has taken place. And it may possibly be thanks to Johan Lundberg, at least partly. Together with some colleagues, he published a study on depressed patients two years ago in which they had looked at how CBT via computers, known as online CBT, affected how the brain processes serotonin. They were able to demonstrate that online treatment conducted over the course of 15 weeks reduced binding to the serotonin receptor 5-HT1B in the brain stem, where the receptor has a moderating effect, by 33 per cent. This means that both drug treatment and therapy have an effect on the same receptor, although in different parts of the brain. It is now no longer so much a question of which treatments are best, rather how they can reinforce one another.

“There is now quite a large consensus that the chances of getting help with your depression increases if drugs are used in combination with CBT, compared with one or the other being provided alone,” says Johan Lundberg.

And with the modern method of online CBT, it is also possible to provide significantly more opportunities to try this combination, even in sparsely populated areas.

There is extensive research being conducted into depression and its treatment and this is taking researchers down many interesting paths. Aleksander Mathé is a senior professor of psychiatry at the Department of Clinical Neuroscience at Karolinska Institutet. He has devoted many years of research to the endogenous protein neuropeptide Y (NPY), which he argues plays a central role in depression. He has published several animal studies that show NPY is reduced in depressed rats and rats with post-traumatic stress disorder, that young rats who are separated from their mothers become behaviourally depressed and have reduced NPY levels, but also that the protein plays a role in the glutamate system.

“I see it being highly probable that the glutamate system is a main factor in depression and that NPY impairs the release of glutamate in some way. Of course, it remains to be shown that this also applies to humans and not just rats,” he says.

However, Aleksander Mathé points out that the NPY molecule has exactly the same sequence of amino acids in rats as it does in humans. The neuropeptide has thus not been changed at all through evolution.

“This gives us more hope that what we see in rats could also apply to humans,” he says.

The peptide is now being tested on depressed patients in Sweden and on patients with post-traumatic stress disorder in the United States, and researchers have seen results that point to them having identified genes that are activated when there is an antidepressant response.

Before the summer, they hope to be able to open the code in order to see which patients have received the peptide and which have received the placebo, so it can be seen if there actually was an effect. But he is already cautiously optimistic.

“The procedure works well and without side effects. There is much to indicate that NPY is a key protein in depression, but I do not believe it is that simple. As is often the case in neurological research, the circumstances are more complicated and involve the interaction of various substances in specific regions of the brain.”

HOWEVER, THERE IS quite a long way to go before NPY can be regarded as a treatment, even if the results of the first study are good. And this research is expensive; this study alone has cost over two million kroner, he explains.

“My greatest concern is finding support for my research. We have now applied for funding for the next stage,” says Alexander Mathé.

But he has other interesting projects underway. In a partnership with researchers in Rome, he has been able to demonstrate in animal models that a relatively common food supplement called L-acetylkarnitine (LAC) has a rapid antidepressant effect via epigenetic mechanisms on a receptor in the glutamate system. Aleksander Mathé hopes to also conduct future tests of LAC on humans.

If it is shown that he is correct in one of these projects, this can be an interesting situation. Neither NPY nor LAC can be patented, which means that no one can obtain the exclusive rights to the substances, something which could make the treatments cheap and available to millions of people with depression. The problem is simply that it is difficult to obtain the money required to develop a treatment.

“Depression and bipolar disorder cost society significantly more than diabetes and cancer, at the same time at there is less research funding for these areas,” he says.

Genetics or environment?

Although there is much uncertainty about the biological mechanisms underlying depression, the researchers have a quite clear understanding of the principles that lie behind the illness's development. They contend that there is an interaction between the susceptibility a person has and the level of depression-inducing stress a person is subject to.

Susceptibility is determined partly by pure genetics and partly by epigenetics, which is in turn dependent on the environment. There are known mutations that are inherited and make a person more susceptible to depression. But in recent years, researchers have also come to understand that a detrimental environment during intra-uterine life or early childhood can lead to epigenetic changes that also increase susceptibility, i.e. that certain genes, which we all have, are turned either on or off as a result of the detrimental environment.

The final pieces of the jigsaw puzzle concern the environment the person lives in, what level of depression-inducing stress the environment entails. In this context, stress denotes everything that pushes up the cortisol levels in the body, which can be anything, from work-related stress or existential angst, to the death of a loved one. In simple terms, if the stress is greater than the individual's susceptibility can cope with, there is a high risk that it will result in depression.